The significance of JAK2-positive test results in a healthy patient

Josef Prchal, MD
The Charles A. Nugent, M.D., and Margaret Nugent Endowed Professor at University of Utah & Huntsman Cancer Center

This month Josef Prchal, MD, discusses the significance of JAK2-positive test results in a healthy patient.

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Another clinician ordered a JAK2 test on a patient for unclear reasons. It was positive. The patient’s counts are normal, and there are no thromboembolic events. What is the significance of this? Should anything be done?


Our knowledge of clonal hematopoiesis of indeterminate potential (CHIP) is still evolving. However, we are gaining more data due to the increasing number of persons undergoing DNA evaluation by whole genome sequencing. These evaluations of their germline DNA have also revealed the presence of acquired somatic mutations, such as JAK2, DNMTA3A and TET genes. These mutations were previously thought to be specific for and diagnostic of myeloid malignancies, as they were originally found in patients with morphological, laboratory, and clinical evidence of myeloid malignancies. However, more recently, these mutations have been found by chance in otherwise-healthy people with normal laboratory and clinical findings; indeed, this patient was one of these.

Our knowledge of this entity indicates that some of the patients with JAK2V617F or TET2 mutations who have no clinical evidence of myeloproliferative neoplasm (MPN) on presentation never develop MPN, but some of them do. These patients have an increased risk of cardiovascular disease. Current evidence suggests that there may be a common pathophysiology between cardiovascular disease and MPN; indeed, both of them are associated with augmentation of inflammation. Animal studies also demonstrate that the presence or introduction of these CHIP somatic mutations also increases risk of cardiovascular disease.

No immediate treatment is needed, but follow-up is advised. Whether the CHIP mutations are also associated with an increased family prevalence of these mutations is not clear. The MPNs characterized by JAK2, CALR, and cMPL mutations are associated with increased risk of MPNs in other family members. While these are acquired mutations, there must be some yet-to-be defined family predisposition to acquire these somatic mutations and it remains to be established if that is also true for CHIP mutations.

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I have a 42-year-old female patient who has had very low B12 levels for at least a decade. This is the first time she has seen a hematologist. She does not have persistent anemia or red cell macrocytosis. She has no neurologic symptoms. Her methylmalonic acid levels and B12-binding capacity have been normal. She has had a lot of gastrointestinal issues and, at various times, small bowel Crohn disease as well as small intestine bacterial overgrowth, which have required therapy. At this time, she is not on any treatment other than dietary restrictions and desipramine. Serology for pernicious anemia and bowel biopsies looking for celiac disease have been normal.

In the past her B12 level has increased moderately when given supplementation, but she does not tolerate parenteral, oral, or nasal supplementation so stopped them. As far as she knows, there is no family history of B12 issues. My best guess is that she has some form of B12-binding protein abnormality that is not of any functional consequence. I tried to find a way to assay for transcobalamin 1 but have not had success. Any suggestions regarding further testing, if needed, or management are welcomed.

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